Allostery, engineering and inhibition of tryptophan synthase

The final two steps of tryptophan biosynthesis are catalyzed by the enzyme tryptophan synthase (TS), composed of alpha (αTS) and beta (βTS) subunits. Recently, experimental and computational methods have mapped “allosteric networks” that connect the αTS and βTS active sites. In αTS, allosteric networks change across the catalytic cycle, which might help drive the conformational changes associated with its function. Directed evolution studies to increase catalytic function and expand the substrate profile of stand-alone βTS have also revealed the importance of αTS in modulating the conformational changes in βTS. These studies also serve as a foundation for the development of TS inhibitors, which can find utility against Mycobacterium tuberculosis and other bacterial pathogens.